1. Field of the Invention
This invention relates to irrigating solutions for use within the human body and more particularly to solutions useful for irrigating tissues during surgery, such as ophthalmic, neural, cardiovascular or otic surgery.
2. Discussion of Related Art
Any scission into the body is detrimental and invariably results in cell loss. The need to keep cell loss to a minimum is particularly crucial during any surgical procedure performed on delicate and irreplaceable tissues, for example, ophthalmic or nerve tissue.
The cornea of the eye is comprised of five layers: epithelium, Bowman's membrane, stroma, Descemet's membrane, and endothelium. The endothelium layer is particularly vulnerable to trauma, and since this layer is only a single cell in depth, protection of the endothelium is particularly important because endothelial cells are infrequently, if ever, replaced as a normal process in adult life. The corneal endothelium is principally responsible for maintaining proper hydration of the stromal layer. The stromal layer has a tendency to imbibe fluid, a tendency which is counterbalanced by outward fluid transport via the endothelium. If the proper fluid balance is not maintained in the stromal layer, the cornea thickens and the characteristic transparency of the cornea is lost. Accordingly, cell loss or damage in the endothelial layer results in decreased vision. Failure of the endothelium to perform its fluid transport function for even short periods of time will result in corneal thickening and visual clouding. Because of the importance and vulnerability of the endothelial layer, it is necessary during eye surgery, such as cataract and retinal surgery or corneal transplants, to make provisions for the protection of the endothelial cells.
A significant factor causing cell loss during tissue scission is the traumatic change in environment experienced by the cells. Exposure to the atmosphere presents a far different environment for internal cells than is provided by the natural fluids in which they are bathed. To simulate the natural cellular environment during surgery thereby preventing cell damage, exposed tissue is frequently irrigated in solutions which attempt to approximate the chemical composition and/or physical properties of natural body fluids. The value of bathing ophthalmic tissue during surgery to prevent cell damage has long been recognized. For internal ocular tissues, such as the endothelium, the aqueous humor is the natural bathing fluid. Therefore, an ideal ophthalmic irrigating solution should simulate or surpass the cell preservation properties of the aqueous humor.
Of primary concern for any tissue irrigating solution is that the osmolality of the solution be generally isotonic relative to cellular fluids, so as to maintain equal osmotic pressure within and without the cell membranes. To this end, one of the early ophthalmic irrigating solutions was isotonic (0.9%) saline. However, it has long been recognized that isotonic saline is quite inadequate as an ophthalmic irrigating solution because its use has been shown to result in endothelial cell swelling, cell damage, and consequent corneal clouding.
Because of the inadequacy of isotonic saline, various alternative electrolyte solutions have been proposed as irrigating solutions, particularly ophthalmic irrigating solutions which more closely resemble the aqueous humor and prevent or reduce cell damage and corneal clouding. Standard electrolyte solutions primarily intended for injection, such as Ringer's solution and lactated Ringer's solution, have been used as ophthalmic irrigating solutions because they are readily available and are sterile.
An electrolyte solution specifically intended for ophthalmic irrigation is available from Alcon Laboratories, Inc. as BSS.RTM.. That solution contains the essential ions calcium, sodium, potassium, magnesium and chloride in generally optimal concentrations for ocular tissue. In addition the solution contains acetate and citrate, natural components of tear fluid.
Electrolyte solutions used for ophthalmic irrigation such as lactated Ringer's solution and balanced salt solutions represent improvements over normal saline because they provide necessary ions in addition to the sodium and chloride ions provided by isotonic saline. For example, magnesium is an important cofactor for adenosine triphosphatase, an enzyme which plays an important role in mediating the fluid transport pump in the eye. Calcium is necessary to maintain the endothelial junction, and potassium is an important factor in many biochemical processes. Moreover, the fluid transport pump of the endothelium requires a proper sodium, potassium ion ratio (Na.sup.+ /K.sup.+) to function. These additions to previously known electrolyte solutions used to irrigate ocular tissue have reduced, but not eliminated, corneal swelling and cell damage during surgery.
The need for improved ophthalmic irrigating solutions continues, particularly in view of new surgical techniques which may probe deeper into the eye requiring several hours of operating time. For example, surgical advances now permit surgery in the vitreous (posterior) chamber to remove opacified vitreous humor or to repair retinal detachment. Such operations can require up to three hours. The risk of damage to internal cells resulting from exposure during surgery increases the longer the cells are exposed.
During eye surgery and particularly during surgery which requires extended periods of time, proper electrolytic balance alone is insufficient to protect the corneal endothelium. To prevent cell damage and maintain proper corneal thickness, an irrigating solution, in addition to maintaining electrolytic balance, must provide metabolic support and must particularly provide factors needed for the enzyme-mediated sodium/potassium ion pump system through which excess fluid is removed from the stroma.
Factors which have been determined to be necessary for sustained metabolism of endothelial cells include dextrose, glutathione and bicarbonate. All have been shown to be important in maintaining the structural integrity of endothelial cells. Dextrose provides an energy source for the cells by serving as a substrate for various metabolic pathways; and glutathione has been shown to aid the adenosine-triphosphatase mediated metabolic pump by maintaining the proper sodium, potassium ion ratio. In addition, bicarbonate is useful in maintaining proper pH of the irrigating solution.
Glutathione bicarbonate-Ringer's solution (GBR) has incorporated the above-mentioned factors and is effective in maintaining corneal thickness and endothelial cell integrity for up to three hours. However, its use has been limited for reasons of sterility and stability.
Sterility of an ophthalmic irrigating solution is absolutely essential. Although a solution will perfuse the eye in essentially a closed system, even a small number of microorganisms can produce an overwhelming endophthalmitis. Therefore, it is important that irrigating solutions be free of pathogens such as pseudomonas, an organism that has very few metabolic requirements and can grow with a minimal nutrient supply; see J. Worst, American Intraocular Implant Society Journal (January, 1978) reporting on a series of infections in Europe due to pseudomonas-contaminated irrigating solutions. Sterility can be ensured through prepackaging so that quality and sterility can be closely monitored and tested.
A significant problem with GBR is that it may not be prepackaged due to the long term incompatibility and/or instability of its various moieties. Of the moieties added to Ringer's solution to formulate GBR, bicarbonate is perhaps the most important, McEnerney et al. Simplification of Glutathione-Bicarbonate Ringer Solution: Its Effect on Corneal Thickness, Investigative Ophthalmology and Visual Science, 16, No. 7 (Jul. 1977). Unfortunately the bicarbonate as well as the phosphate in a bicarbonate-phosphate buffer system form insoluble precipitates with magnesium and calcium ions. Although precipitation is not a problem in freshly prepared solutions at the ionic concentrations useful in ophthalmic irrigation, long-term storage is proscribed. As insoluble crystals introduced into the eye will cloud vision, the importance of keeping a tissue irrigating solution free of insoluble precipitates may be readily appreciated. For discussion relating to precipitation of calcium bicarbonate from Ringer's solution containing sodium bicarbonate and dextrose see O'Malley, Salt Contamination of the Eye--An Infusion Hazard, Ocutome/Fragmatome Newsletter, 4, No. 14, 1979.
A further factor which proscribes long-term storage of GBR is the unavailability of a proper pH at which all of the moieties are stable. Several moieties of GBR are unstable at the physiological pH of about 7.4. Below a pH of about 8 bicarbonate generally decomposes producing CO.sub.2 and resulting both in a loss of bicarbonate and increased pH. On the other hand, glucose is stable at a pH of less than about 6. Glutathione, while biologically effective either in reduced or oxidized form, is preferred in the oxidized form because the reduced form quickly oxidizes in aqueous solutions, preventing proper labeling of the irrigating solution. However, above pH 5 in admixture with all other components, oxidized glutathione (glutathione disulfide) is unstable over extended periods of time and as a result will gradually decrease to an unacceptably low level.
Problems due to the formation of insoluble precipitates and glutathione instability in an irrigating solution were resolved as set forth in two patents, U.S. Pat. No. 4,550,022 and U.S. Pat. No. 4,443,432, issued to Garabedian, et al. on Oct. 29, 1985 and Apr. 17, 1984, respectively. The entire contents of these two patents are hereby incorporated in the present specification by reference. In those patents the problems of precipitates and instability were surmounted by recognizing the causes of the problems and devising a two-part product approach wherein the parts are combined prior to use. Calcium and magnesium ions are present in one sterile solution which is acidic and separate from a basic solution containing phosphate and bicarbonate ions. Glutathione, being more stable at lower pH, is present in the acidic solution. The two solutions are then mixed just prior to use, preferably within 24 hours of surgery.
Although the two-part solutions described in U.S. Pat. Nos. 4,550,022 and 4,443,432 provide a way to store two stable, sterile solutions that upon mixing provide tissue irrigating solutions having short term stability, there is still a need for improved tissue irrigating solutions and for single solution products having long term stability. Single solution products are desirable due to the relative ease of manufacture and use, and elimination of the risks of possible contamination during mixing.
Accordingly, it is an objective to provide improved irrigating solutions having long term stability which provide for protection of ophthalmic and other tissues by providing the necessary electrolyte and metabolic support during surgery.